Inhaled corticosteroids (ICS) are effective in controlling airway inflammation and asthma symptoms, but multiple long term studies indicate that ICS do not change the natural course of disease progression. This leaves unanswered the question of identifying novel pathways that might account for airway remodeling and persistent asthma. Here we propose that aberrant remodeling of the airway might be initiated by humoral features of an inflammatory cellular microenvironment, but is perpetuated and amplified by changes in the physical microenvironment. We propose here the notion that passive matrix distensibility and active matrix stretch, as are found in the normal airway in vivo, tend to be protective against aberrant remodeling. This hypothesis is novel, is mechanistic and is testable in three experimental aims. Aim 1 tests the hypothesis that a substrate of physiological distensibility is protective against a proliferative / synthetic phenotype. Aim 2 tests the hypothesis that a substrate with physiological levels of stretch causes cytoskeletal fluidization that is also protective against a proliferative / synthetic phenotype. Aim 3 asks the question, Do responses to the physical microenvironment differ between cells resident in the normal versus the asthmatic airway. That is to say, is the resident cell in the asthmatic airway a victim of its physical microenvironment? Or instead, do innate differences dominate the cellular phenotype? These aims will be carried out in the isolated human lung fibroblast, and the generality of the results will be confirmed in the human airway smooth muscle cell, both of which play central roles in remodeling of the asthmatic airway. PUBLIC HEALTH RELEVANCE: Just as they are influenced by a chemical microenvironment defined by ligation of humoral factors and matrix- associated proteins, cells resident within the airway may be influenced by a mechanical microenvironment defined by physical forces. The role of the mechanical microenvironment represents a new dimension with the potential of deepening our understanding of the behavior of the normal airway and its remodeling in persistent asthma.